4.1. Therapeutic indications

Treatment of essential hypertension.

Add-on therapy

Sevikar HCT is indicated in adult patients whose blood pressure is not adequately controlled on the combination of olmesartan medoxomil and amlodipine taken as dual-component formulation.

Substitution therapy

Sevikar HCT is indicated as substitution therapy in adult patients whose blood pressure is adequately controlled on the combination of olmesartan medoxomil, amlodipine and hydrochlorothiazide, taken as a dual-component (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and a single-component formulation (hydrochlorothiazide or amlodipine).

4.2. Posology and method of administration

Posology

Adults

The recommended dose of Sevikar HCT is 1 tablet per day.

Add-on therapy

Sevikar HCT 20 mg/5 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled on olmesartan medoxomil 20 mg and amlodipine 5 mg taken as dual-component combination.

Sevikar HCT 40 mg/5 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled on olmesartan medoxomil 40 mg and amlodipine 5 mg taken as dual-component combination or in patients whose blood pressure is not adequately controlled on Sevikar HCT 20 mg/5 mg/12.5 mg.

Sevikar HCT 40 mg/5 mg/25 mg may be administered in patients whose blood pressure is not adequately controlled on Sevikar HCT 40 mg/5 mg/12.5 mg.

Sevikar HCT 40 mg/10 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled on olmesartan medoxomil 40 mg and amlodipine 10 mg taken as dual-component combination or by Sevikar HCT 40 mg/5 mg/12.5 mg.

Sevikar HCT 40 mg/10 mg/25 mg may be administered in patients whose blood pressure is not adequately controlled on Sevikar HCT 40 mg/10 mg/12.5 mg or by Sevikar HCT 40 mg/5 mg/25 mg.

A step-wise titration of the dosage of the individual components is recommended before changing to the triple-component combination. When clinically appropriate, direct change from dual-component combination to the triple-component combination may be considered.

Substitution therapy

Patients controlled on stable doses of olmesartan medoxomil, amlodipine and hydrochlorothiazide taken at the same time as a dual-component (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and a single-component formulation (hydrochlorothiazide or amlodipine) may be switched to Sevikar HCT containing the same component doses.

The maximum recommended dose of Sevikar HCT is 40 mg/10 mg/25 mg per day.

Elderly (age 65 years or over)

Caution, including more frequent monitoring of blood pressure, is recommended in elderly people, particularly at the maximum dose of Sevikar HCT 40 mg/10 mg/25 mg per day.

An increase of the dosage should take place with care in elderly people (see sections 4.4 and 5.2).

Very limited data are available on the use of Sevikar HCT in patients aged 75 years or older. Extreme caution, including more frequent monitoring of blood pressure, is recommended.

Renal impairment

The maximum dose in patients with mild to moderate renal impairment (creatinine clearance of 30 – 60 mL/min) is Sevikar HCT 20 mg/5 mg/12.5 mg, owing to limited experience of the 40 mg olmesartan medoxomil dosage in this patient group.

Monitoring of serum concentrations of potassium and creatinine is advised in patients with moderate renal impairment.

The use of Sevikar HCT in patients with severe renal impairment (creatinine clearance < 30 mL/min) is contraindicated (see sections 4.3, 4.4 and 5.2).

Hepatic impairment

Sevikar HCT should be used with caution in patients with mild hepatic impairment (see sections 4.4 and 5.2).

In patients with moderate hepatic impairment the maximum dose should not exceed Sevikar HCT 20 mg/5 mg/12.5 mg once daily. Close monitoring of blood pressure and renal function is advised in patients with hepatic impairment.

As with all calcium antagonists, amlodipine's half-life is prolonged in patients with impaired liver function and dosage recommendations have not been established. Sevikar HCT should therefore be administered with caution in these patients. The pharmacokinetics of amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose and titrated slowly in patients with impaired liver function.

Use of Sevikar HCT is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2), cholestasis or biliary obstruction (see section 4.3).

Paediatric population

Sevikar HCT is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy.

Method of administration:

The tablet should be swallowed with a sufficient amount of fluid (e. g. one glass of water). The tablet should not be chewed and should be taken at the same time each day.

Sevikar HCT can be taken with or without food.

4.3. Contraindications

Hypersensitivity to the active substances, to dihydropyridine derivates or to sulfonamide-derived substances (since hydrochlorothiazide is a sulfonamide-derived drug) or to any of the excipients listed in section 6.1.

Severe renal impairment (see sections 4.4 and 5.2).

Refractory hypokalaemia, hypercalcaemia, hyponatraemia and symptomatic hyperuricaemia.

Severe hepatic insufficiency, cholestasis and biliary obstructive disorders (see section 5.2).

2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6).

The concomitant use of Sevikar HCT with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2) (see sections 4.5 and 5.1).

Due to the amlodipine component, Sevikar HCT is contraindicated in patients with:

- Shock (including cardiogenic shock).

- Severe hypotension

- Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis).

- Haemodynamically unstable heart failure after acute myocardial infarction.

4.4. Special warnings and precautions for use

Patients with hypovolaemia or sodium depletion:

Symptomatic hypotension may occur in patients who are volume and/or sodium depleted as a result of vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting, especially after the first dose. Correction of this condition prior to administration of Sevikar HCT or close medical supervision at the start of the treatment is recommended.

Other conditions with stimulation of the renin-angiotensin-aldosterone system:

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e. g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure.

Renovascular hypertension:

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation:

When Sevikar HCT is used in patients with impaired renal function, periodic monitoring of serum concentrations of potassium and creatinine is recommended.

Use of Sevikar HCT is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections 4.2, 4.3 and 5.2).

Thiazide diuretic-associated azotaemia may occur in patients with impaired renal function.

If progressive renal impairment becomes evident, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy.

There is no experience of the administration of Sevikar HCT in patients with a recent kidney transplant or in patients with end-stage renal impairment (i. e. creatinine clearance < 12 mL/min).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS):

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Hepatic impairment:

Exposure to amlodipine and olmesartan medoxomil is increased in patients with hepatic impairment (see section 5.2).

Furthermore, minor alterations of fluid and electrolyte balance during thiazide therapy may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

Care should be taken when Sevikar HCT is administered in patients with mild to moderate hepatic impairment.

In patients with moderate hepatic impairment, the dose of olmesartan medoxomil should not exceed 20 mg (see section 4.2).

In patients with impaired hepatic function, amlodipine should be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose.

Use of Sevikar HCT is contraindicated in patients with severe hepatic impairment, cholestasis or biliary obstruction (see section 4.3).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:

Due to the amlodipine component of Sevikar HCT, as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism:

Patients with primary aldosteronism generally will not respond to anti-hypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Sevikar HCT is not recommended in such patients.

Metabolic and endocrine effects:

Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required (see section 4.5). Latent diabetes mellitus may become manifest during thiazide therapy.

Increases in cholesterol and triglyceride levels are undesirable effects known to be associated with thiazide diuretic therapy.

Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy.

Electrolyte imbalance:

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8).

The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5).

Conversely, due to antagonism at the angiotensin-II receptors (AT1) through the olmesartan medoxomil component of Sevikar HCT hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. Close monitoring of serum potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes and other medicinal products that may increase serum potassium levels (e. g. heparin) should be co-administered cautiously with Sevikar HCT (see section 4.5) and with frequent monitoring of potassium levels.

There is no evidence that olmesartan medoxomil would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment.

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism.

Hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Dilutional hyponatraemia may occur in oedematous patients in hot weather.

Lithium:

As with other angiotensin II receptor antagonists, the coadministration of Sevikar HCT and lithium is not recommended (see section 4.5).

Heart failure:

As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals.

In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death.

Patients with heart failure should be treated with caution. In a long-term, placebo controlled study of amlodipine in patients with severe heart failure (NYHA III and IV), the reported incidence of pulmonary oedema was higher in the amlodipine group than in the placebo group (see section 5.1). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Sprue-like enteropathy:

In very rare cases severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, and in the absence of other apparent etiologies, olmesartan treatment should be immediately discontinued and should not be restarted. If diarrhoea does not improve during the week after the discontinuation, further specialist (e.g. a gastro-enterologist) advice should be considered.

Intestinal angioedema:

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, [including olmesartan medoxomil] (see section 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, olmesartan medoxomil should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

Choroidal Effusion, Acute Myopia and Secondary Angle-Closure Glaucoma:

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in choroidal effusion with visual field defect, acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy (see section 4.8).

Pregnancy:

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonists therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Paediatric population:

Sevikar HCT is not indicated in children and adolescents under the age of 18 years.

Elderly:

In the elderly, increase of the dosage should take place with care (see section 5.2).

Photosensitivity:

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction occurs during treatment with Sevikar HCT, it is recommended to stop the treatment. If re-administration of the diuretic is deemed necessary, it is recommended to protect the areas exposed to the sun or to artificial UVA.

Non-melanoma skin cancer:

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.

Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

Acute Respiratory Toxicity:

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, Sevikar HCT should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

Other:

As with any antihypertensive agent, excessive blood pressure reduction in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

As with all other angiotensin II receptor antagonists, the blood pressure lowering effect of olmesartan is somewhat less in black patients than in non-black patients, however, this effect was not seen in one of the three clinical trials with Sevikar HCT that included black patients (30 %), see also section 5.1.

This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Potential interactions related to the Sevikar HCT combination:

Concomitant use not recommended

Lithium:

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and, rarely, with angiotensin II receptor antagonists. In addition, renal clearance of lithium is reduced by thiazides and consequently the risk of lithium toxicity may be increased. Therefore use of Sevikar HCT and lithium in combination is not recommended (see section 4.4). If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Baclofen:

Potentiation of antihypertensive effect may occur.

Non-steroidal anti-inflammatory medicinal products:

NSAIDs (i.e. acetylsalicylic acid (> 3 g/day), COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of thiazide diuretics and angiotensin II receptor antagonists.

In some patients with compromised renal function (e. g. dehydrated patients or elderly people with compromised renal function) the co-administration of angiotensin II receptor antagonists and agents that inhibit cyclooxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter.

Concomitant use to be taken into account

Amifostine:

Potentiation of antihypertensive effect may occur.

Other antihypertensive agents:

The blood pressure lowering effect of Sevikar HCT can be increased by concomitant use of other antihypertensive medicinal products.

Alcohol, barbiturates, narcotics or antidepressants:

Potentiation of orthostatic hypotension may occur.

Potential interactions related to olmesartan medoxomil:

Concomitant use not recommended

ACE-inhibitors, angiotensin II receptor blockers or aliskiren:

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Medicinal products affecting potassium levels:

Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e. g. heparin, ACE inhibitors) may lead to increases in serum potassium (see section 4.4). If medicinal products that affect potassium are to be prescribed in combination with Sevikar HCT, monitoring of serum potassium is advised.

Additional information

Bile acid sequestering agent colesevelam:

Concurrent administration of the bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan and reduces t1/2. Administration of olmesartan medoxomil at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Administering olmesartan medoxomil at least 4 hours before the colesevelam hydrochloride dose should be considered (see section 5.2).

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed.

Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin.

Coadministration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.

Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and medicinal products metabolised by the above cytochrome P450 enzymes are expected.

Potential interactions related to amlodipine

Concomitant use requiring caution

Effects of other medicinal products on amlodipine

CYP3A4 inhibitors:

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic variations may be more pronounced in the elderly. There is an increased risk of hypotension. Close observation of patients is recommended and dose adjustment may thus be required.

CYP3A4 inducers:

Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, hypericum perforatum).

Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Effects of amlodipine on other medicinal products

The blood pressure-lowering effect of amlodipine adds to the blood pressure-lowering effects of other antihypertensive agents.

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.

Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Mechanistic Target of Rapamycin (mTOR) Inhibitors: mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.

Cyclosporine: In a prospective study in renal transplant patients, an average 40% increase in trough cyclosporine levels was observed when used concomitantly with amlodipine. The co-administration of Sevikar HCT with cyclosporine may increase exposure to cyclosporine. Monitor trough cyclosporine levels during concomitant use and cyclosporine dose reductions should be made as necessary.

Potential interactions related to hydrochlorothiazide:

Concomitant use not recommended

Medicinal products affecting potassium levels:

The potassium-depleting effect of hydrochlorothiazide (see section 4.4) may be potentiated by the coadministration of other medicinal products associated with potassium loss and hypokalaemia (e. g. other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium or salicylic acid derivatives). Such concomitant use is therefore not recommended.

Concomitant use requiring caution

Calcium salts:

Thiazide diuretics may increase serum calcium owing to decreased excretion. If calcium supplements must be prescribed, serum calcium should be monitored and calcium dosage adjusted accordingly.

Cholestyramine and colestipol resins:

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.

Digitalis glycosides:

Thiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis-induced cardiac arrhythmias.

Medicinal products affected by serum potassium disturbances:

Periodic monitoring of serum potassium and ECG is recommended when Sevikar HCT is administered with medicinal products affected by serum potassium disturbances (e. g. digitalis glycosides and antiarrhythmics) and with the following torsades de pointes (ventricular tachycardia)-inducing medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes (ventricular tachycardia):

- Class Ia antiarrhythmics (e. g. quinidine, hydroquinidine, disopyramide).

- Class III antiarrhythmics (e. g. amiodarone, sotalol, dofetilide, ibutilide).

- Some antipsychotics (e. g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).

- Others (e. g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine, sparfloxacin, terfenadine, vincamine IV).

Non-depolarizing skeletal muscle relaxants (e. g. tubocurarine):

The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.

Anticholinergic agents (e. g. atropine, biperiden):

Increase of the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.

Antidiabetic medicinal products (oral agents and insulin):

The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic medicinal product may be required (see section 4.4).

Metformin:

Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.

Beta-blockers and diazoxide:

The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

Pressor amines (e. g. noradrenaline):

The effect of pressor amines may be decreased.

Medicinal products used in the treatment of gout (e. g. probenecid, sulfinpyrazone and allopurinol):

Dosage adjustment of uricosuric medicinal products may be necessary since hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Coadministration of a thiazide may increase the incidence of hypersensitivity reactions to allopurinol.

Amantadine:

Thiazides may increase the risk of adverse effects caused by amantadine.

Cytotoxic agents (e. g. cyclophosphamide, methotrexate):

Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate their myelosuppressive effects.

Salicylates:

In case of high dosages of salicylates hydrochlorothiazide may enhance the toxic effect of the salicylates on the central nervous system.

Methyldopa:

There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine:

Concomitant treatment with cyclosporine may increase the risk of hyperuricaemia and gout-type complications.

Tetracyclines:

Concomitant administration of tetracyclines and thiazides increases the risk of tetracycline-induced increase in urea. This interaction is probably not applicable to doxycycline.

4.6. Fertility, pregnancy and lactation

Pregnancy

The use of Sevikar HCT is contra-indicated during the 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4). Given the effects of the individual components in this combination product on pregnancy, the use of Sevikar HCT is not recommended during the first trimester of pregnancy (see section 4.4).

Olmesartan medoxomil

The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contra-indicated during the 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin receptor blocker therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments, which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II receptor antagonists therapy during the 2nd and 3rd trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also section 5.3).

Should exposure to angiotensin II receptor antagonists have occurred from the 2nd trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants, whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension (see also sections 4.3 and 4.4).

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the 2nd and 3rd trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or pre-eclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Amlodipine

Data on a limited number of exposed pregnancies do not indicate that amlodipine or other calcium receptor antagonists have a harmful effect on the health of the fetus. However, there may be a risk of prolonged delivery.

Breastfeeding

During breastfeeding, Sevikar HCT is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

Olmesartan is excreted into the milk of lactating rats. However, it is not known whether olmesartan passes into human milk.

Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3 – 7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production.

The use of Sevikar HCT during breastfeeding is not recommended. If Sevikar HCT is used during breastfeeding, doses should be kept as low as possible.

Fertility

Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers.

Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

However, it should be borne in mind that dizziness, headache, nausea or fatigue may occasionally occur in patients taking antihypertensive therapy and that these symptoms may impair the ability to react. Caution is recommended especially at the start of treatment.

4.8. Undesirable effects

The safety of Sevikar HCT was investigated in clinical trials in 7826 patients receiving olmesartan medoxomil in combination with amlodipine and hydrochlorothiazide.

Adverse reactions from clinical trials, post-authorization safety studies and spontaneous reporting are summarized in table 1 for Sevikar HCT as well as for the individual components olmesartan medoxomil, amlodipine and hydrochlorothiazide based on the known safety profile of the single components.

The most commonly reported adverse reactions during treatment with Sevikar HCT are peripheral oedema, headache and dizziness.

The following terminologies have been used in order to classify the occurrence of undesirable effects:

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Table 1: Overview of adverse reactions with Sevikar HCT and the single components

MedDRA

System Organ Class

Adverse reactions

Frequency

Sevikar HCT

Olmesartan

Amlodipin

HCTZ

Infections and infestations

Upper respiratory tract infection

Common

Nasopharyngitis

Common

Urinary tract infection

Common

Common

Sialadenitis

Rare

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma)

Not known

Blood and lymphatic system disorders

Leucopenia

Very rare

Rare

Thrombocytopenia

Uncommon

Very rare

Rare

Bone marrow depression

Rare

Neutropenia/Agranulocytosis

Rare

Haemolytic anaemia

Rare

Aplastic anaemia

Rare

Immune system disorders

Anaphylactic reaction

Uncommon

Drug hypersensitivity

Very rare

Metabolism and nutrition disorders

Hyperkalaemia

Uncommon

Rare

Hypokalaemia

Uncommon

Common

Anorexia

Uncommon

Glycosuria

Common

Hypercalcaemia

Common

Hyperglycaemia

Very rare

Common

Hypomagnesaemia

Common

Hyponatriaemia

Common

Hypochloraemia

Common

Hypertriglyceridaemia

Common

Very common

Hypercolesterolaemia

Very common

Hyperuricaemia

Common

Very common

Hypochloraemic alkalosis

Very rare

Hyperamylasaemia

Common

Psychiatric disorders

Confusional state

Rare

Common

Depression

Uncommon

Rare

Apathy

Rare

Irritability

Uncommon

Restlessness

Rare

Mood changes (including anxiety)

Uncommon

Sleep disorders (including insomnia)

Uncommon

Rare

Nervous system disorders

Dizziness

Common

Common

Common

Common

Headache

Common

Common

Common

Rare

Postural dizziness

Uncommon

Presyncope

Uncommon

Dysgeusia

Uncommon

Hypertonia

Very rare

Hypoaesthesia

Uncommon

Paraesthesia

Uncommon

Rare

Peripheral neuropathy

Very rare

Somnolence

Common

Syncope

Uncommon

Convulsions

Rare

Loss of appetite

Uncommon

Tremor

Uncommon

Extrapyramidal disorder

Not known

Eye disorders

Visual disturbance (including diplopia, blurred vision)

Common

Rare

Lacrimation decreased

Rare

Worsening of myopia

Uncommon

Xanthopsia

Rare

Acute myopia, acute angle-closure glaucoma (see section 4.4.)

Not known

Choroidal effusion

Not known

Ear and labyrinth disorders

Vertigo

Uncommon

Uncommon

Rare

Tinnitus

Uncommon

Cardiac disorders

Palpitations

Common

Common

Tachycardia

Uncommon

Myocardial infarction

Very rare

Arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)

Uncommon

Rare

Angina pectoris

Uncommon

Uncommon (incl. aggravation of angina pectoris)

Vascular disorders

Hypotension

Common

Rare

Uncommon

Flushing

Uncommon

Common

Orthostatic hypotension

Uncommon

Vasculitis (including necrotising angiitis)

Very rare

Rare

Thrombosis

Rare

Embolism

Rare

Respiratory, thoracic and mediastinal disorders

Cough

Uncommon

Common

Uncommon

Bronchitis

Common

Dyspnoea

Common

Rare

Pharyngitis

Common

Rhinitis

Common

Uncommon

Acute interstitial pneumonia

Rare

Respiratory distress

Uncommon

Pulmonary oedema

Rare

Acute respiratory distress syndrome (ARDS) (see section 4.4.)

Very rare

Gastrointestinal disorders

Diarrhoea

Common

Common

Common

Nausea

Common

Common

Common

Common

Constipation

Common

Common

Dry mouth

Uncommon

Uncommon

Abdominal pain

Common

Common

Common

Altered bowel habits (including diarrhoea and constipation)

Common

Meteorism

Common

Dyspepsia

Common

Common

Gastritis

Very rare

Gastric irritation

Common

Gastroenteritis

Common

Gingival hyperplasia

Very rare

Paralytic ileus

Very rare

Pancreatitis

Very rare

Rare

Vomiting

Uncommon

Uncommon

Common

Intestinal angioedema (see section 4.4)

Rare

Sprue-like enteropathy (see section 4.4)

Very rare

Hepatobiliary disorders

Hepatitis

Very rare

Jaundice (intrahepatic cholestatic icterus)

Very rare

Rare

Acute cholecystitis

Rare

Autoimmune hepatitis*

Not known

Skin and subcutaneous tissue disorders

Alopecia

Uncommon

Angioedema

Rare

Very rare

Allergic dermatitis

Uncommon

Erythema multiforme

Very rare

Erythema

Uncommon

Cutaneous lupus erythematodes-like reactions

Rare

Exanthema

Uncommon

Uncommon

Exfoliative dermatitis

Very rare

Hyperhydrosis

Uncommon

Photosensitivity reactions

Very rare

Uncommon

Pruritus

Uncommon

Uncommon

Uncommon

Purpura

Uncommon

Uncommon

Quincke oedema

Very rare

Rash

Uncommon

Uncommon

Uncommon

Reactivation of cutaneous lupus erythematodes

Rare

Toxic epidermal necrolysis

Not known

Rare

Skin discoloration

Uncommon

Stevens-Johnson syndrome

Very rare

Urticaria

Uncommon

Uncommon

Uncommon

Musculoskeletal and connective tissue disorders

Muscle spasm

Common

Rare

Common

Joint swelling

Common

Muscular weakness

Uncommon

Rare

Ankle swelling

Common

Arthralgia

Uncommon

Arthritis

Common

Back pain

Common

Uncommon

Paresis

Rare

Myalgia

Uncommon

Uncommon

Skeletal pain

Common

Renal and urinary disorders

Pollakiuria

Common

Increased urinary frequency

Uncommon

Acute renal failure

Rare

Haematuria

Common

Micturition disorder

Uncommon

Nocturia

Uncommon

Interstitial nephritis

Rare

Renal insufficiency

Rare

Rare

Reproductive system and breast disorders

Erectile dysfunction

Uncommon

Uncommon

Uncommon

Gynaecomastia

Uncommon

General disorders and administration site conditions

Asthenia

Common

Uncommon

Common

Peripheral oedema

Common

Common

Fatigue

Common

Common

Common

Chest pain

Common

Uncommon

Fever

Rare

Influenza-like symptoms

Common

Lethargy

Rare

Malaise

Uncommon

Uncommon

Oedema

Very common

Pain

Common

Uncommon

Face oedema

Uncommon

Investigations

Blood creatinine increased

Common

Rare

Common

Blood urea increased

Common

Common

Common

Blood uric acid increased

Common

Blood potassium decreased

Uncommon

Gamma glytamyl transferase increased

Uncommon

Alanine aminotransferase increased

Uncommon

Aspartate aminotransferase increased

Uncommon

Hepatic enzymes increased

Common

Very rare (mostly consistent with cholestatis)

Blood creatine phosphokinase increased

Common

Weight decrease

Uncommon

Weight increase

Uncommon

*Cases of autoimmune hepatitis with a latency of few months to years have been reported post-marketing, that were reversible after the withdrawal of olmesartan.

Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers. Single cases of extrapyramidal syndrome have been reported in patients treated with amlodipine.

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

Further adverse reactions reported in clinical trials or from post marketing experience with a fixed-dose combination of olmesartan medoxomil and amlodipine and not already reported for Sevikar HCT, olmesartan medoxomil monotherapy or amlodipine monotherapy or reported in a higher frequency for the dual combination (Table 2):

Table 2: Combination of olmesartan medoxomil and amlodipine

System Organ Class

Frequency

Adverse reactions

Immune system disorders

Rare

Drug hypersensitivity

Gastrointestinal disorders

Uncommon

Upper abdominal pain

Reproductive system and breast disorders

Uncommon

Libido decreased

General disorders and administration site conditions

Common

Pitting oedema

Uncommon

Lethargy

Musculoskeletal and connective tissue disorders

Uncommon

Pain in extremity

Further adverse reactions reported in clinical trials or from post marketing experience with a fixed-dose combination of olmesartan medoxomil and hydrochlorothiazide and not already reported for Sevikar HCT, olmesartan medoxomil monotherapy or hydrochlorothiazide monotherapy or reported in a higher frequency for the dual combination (Table 3):

Table 3: Combination of olmesartan medoxomil and hydrochlorothiazide

System Organ Class

Frequency

Adverse reactions

Nervous system disorders

Rare

Disturbances in consciousness (such as loss of consciousness)

Skin and subcutaneous tissue disorders

Uncommon

Eczema

Musculosceletal and connective tissue disorders

Uncommon

Pain in extremity

Investigations

Rare

Minor decreases in mean haemoglobin and haematocrit values

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms:

The maximum dose of Sevikar HCT is 40 mg/10 mg/25 mg once daily. There is no information on overdosage with Sevikar HCT in humans. The most likely effect of Sevikar HCT overdosage is hypotension.

The most likely effects of olmesartan medoxomil overdosage are hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurred.

Amlodipine overdosage can be expected to lead to excessive peripheral vasodilatation with marked hypotension and possibly a reflex tachycardia. Marked and potentially prolonged systemic hypotension, up to and including shock with fatal outcome, has been reported.

Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

Overdosage with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis.

The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.

Treatment:

In the event of overdosage with Sevikar HCT, treatment should be symptomatic and supportive. Management depends upon the time since ingestion and the severity of the symptoms.

If intake is recent, gastric lavage may be considered. In healthy subjects, the administration of activated charcoal immediately or up to 2 hours after ingestion of amlodipine has been shown to reduce substantially the absorption of amlodipine.

Clinically significant hypotension due to an overdose of Sevikar HCT requires active support of the cardiovascular system, including close monitoring of heart and lung function, elevation of the extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly.

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. The dialysability of olmesartan or hydrochlorothiazide is unknown.

The degree to which olmesartan and hydrochlorothiazide are removed by haemodialysis has not been established.